Diverse functions of p38? MAPK in T helper differentiation Abstract Mitogen activated protein kinases (MAPK), including ERK, p38 and JNK, represent highly conserved and ubiquitous signaling modules by which cells of all types respond to their extracellular environment. Despite their name, MAPK are involved in many cellular responses in addition to proliferation, including development, survival, apoptosis and transformation, and are activated by many highly diverse stimuli. In the immune system, these include Ag receptors on T and B cells, receptors for numerous cytokines and chemokines on multiple cell types (including T cells), TLRs, and others. Each of the three major MAPK families (ERK, p38 and JNK) consist of 2-4 isoforms, which are encoded by different genes and have distinct, although partially overlapping, patterns of expression. However, in very few cases have distinct functions of specific MAPK isoforms been definitively identified. This revised application is focused on defining the functions of the major p38 isoform p38? in Th1 differentiation and the role(s) of p38? and p38? in regulatory T cell (Treg) differentiation. Our hypothesis is that p38 is essential for the differentiation and effector functions of these subsets of T helper cell types via an essential role in transcriptional networks which direct their differentiation. Naive CD4 T cells have the capacity to differentiate into at least six distinct types of T helper (Th) cells, which are distinguished by their unique functions in response to different types of immune challenges, the cytokines which induce them, and the signaling and transcriptional programs which lead to their development. As presented in the application, we have developed strong evidence that p38? is specifically required for differentiation of Th1 cells and have uncovered possible mechanisms which explain this. We have also developed data that indicates that Tregs utilize both p38? and p38? during development. We will further investigate these issues by identifying mechanisms through which p38? controls the differentiation of Th1 cells, and by determining whether and how p38? and p38? play a role in the differentiation and/or function of Treg. As the functions of p38 isoforms in T helper differentiation remain poorly understood, this project will make a major impact in the field, and will provide the foundation for understanding the role of p38 MAPK in the immune system.